L-19 Pathology of infectious diseases

Viruses: Objectives

• Describe the mechanisms of tissue injury and host reactions induced by viruses.

• Compare the histopathological features of herpes virus, cytomegalovirus, human papillomavirus, and adenovirus, with respect to:

  • Nuclear inclusions
  • Cell size
  • Unique histopathological characteristics

• Recognize the histopathological features of viral infections in images of different tissues.

• Describe the spectrum of inflammatory responses to viral infections, categorized as:

  • Transient infections
  • Chronic latent infections (e.g., Herpes virus, meningitis viruses)
  • Chronic productive infections (e.g., Hepatitis B virus)
  • Transforming infections

Virulence

• One of the key characteristics for an organism to cause disease

• To cause disease, an organism must:

  • Gain access to the body
  • Avoid host defenses
  • Adapt to growth in a human host
  • Exploit human resources

• Virulence reflects both the inherent structures of the offending microbe and its interplay with host defense mechanisms.

Viral Infections

• Viruses have key characteristics:
  • Size ranges from 20 to 300 nm.
  • Genetic material is either RNA or DNA, enclosed in a protein shell.
  • Some viruses possess lipid membrane envelopes.
• Obligate intracellular parasites that cannot metabolize or reproduce independently.
• Achieve replication by invading host cells, hijacking their biosynthetic and metabolic systems to produce viral nucleic acids and proteins.
• Viruses have specific surface proteins that bind to host cell surface proteins, which is exemplified by coronavirus 2 (SARS-CoV-2).

Viral infections and inclusion bodies

• Viruses have inclusion bodies, which are useful for diagnosis.

• Negri bodies are intracytoplasmic inclusion bodies found in rabies virus-infected neurons and are important in diagnosing the disease.

• The viruses and their inclusion bodies:

  • Rabies Virus: Negri bodies are found in the neurons of the hippocampus and cerebellum, demonstrating eosinophilic intracytoplasmic inclusions, which are pathognomonic for rabies infection in animals and humans
  • Cytomegalovirus (CMV): Owl’s eye inclusion bodies are found in the nuclei of infected cells, indicating large, basophilic intranuclear inclusions with a clear halo. These are diagnostic for CMV infection in various tissues.
  • Herpes Simplex Virus (HSV): Cowdry type A bodies are found in the nuclei of infected cells, indicating intranuclear eosinophilic inclusions with margination of chromatin, which are characteristic of acute HSV infection in affected tissues.
  • Human Papillomavirus (HPV): Koilocytes are found in the epithelium (e.g., cervix), indicating cytoplasmic vacuoles, perinuclear halos, and nuclear atypia; observed in HPV-related lesions like warts or cervical dysplasia.
  • Measles Virus: Warthin-Finkeldey cells are frequently found in lymphoid tissue, indicating multinucleated giant cells with eosinophilic inclusions, often diagnostic for measles infection in the sampled lymphoid tissues..
  • Varicella Zoster Virus (VZV): Cowdry Type A bodies are found in nuclei of infected cells, resembling the nuclear characteristics of herpes simplex viral infections. Often seen to diagnose both Varicella (chickenpox) and Herpes Zoster (shingles), diagnosis can be accomplished with a Tzanck smear.

Types of viral infections

• Transient Infections:
  • Examples include Influenza, Rhinovirus, Adenovirus, and Coronaviruses (e.g., SARS).
• Chronic Latent Infections:
  • Examples include Herpes Simplex Viruses (HSVs), Varicella-Zoster Virus (VZV), and Epstein-Barr Virus (EBV).
• Chronic Productive Infections:
  • Hepatitis B Virus is a notable example.
• Transforming Infections:
  • An example includes Human Papillomavirus (HPV).

Transient Viral Infections by Organ System:

• Respiratory:
  • Adenovirus leads to upper and lower respiratory tract infections, conjunctivitis, and diarrhea.
  • Rhinovirus causes upper respiratory tract infections.
  • Influenza viruses A and B cause influenza.
  • Respiratory syncytial virus causes bronchiolitis and pneumonia.
• Systemic with Skin Eruptions:
  • Measles virus results in measles (rubeola).
  • Rubella virus causes German measles (rubella).
  • Varicella-zoster virus causes chickenpox and shingles.
  • Herpes simplex virus 1 causes oral herpes (“cold sore”).
  • Herpes simplex virus 2 causes genital herpes.
• Digestive:
  • Mumps virus causes mumps, pancreatitis, and orchitis.
• Systemic with Hematologic Disorders:
  • Cytomegalovirus leads to cytomegalic inclusion disease.
  • Epstein-Barr virus causes infectious mononucleosis.
  • Human immunodeficiency viruses 1 and 2 lead to acquired immunodeficiency syndrome.
• Arboviral and Hemorrhagic Fevers:
  • Dengue viruses 1 to 4 lead to dengue hemorrhagic fever.
  • Yellow fever virus causes yellow fever.
• Common Arthropod-Borne Viral Diseases in the U.S.A.:
  • Eastern equine encephalitis (EEE), Everglades virus (EVEV), St. Louis encephalitis virus (SLEV), Colorado tick fever, West Nile virus infections, Chikungunya virus disease, and Powassan virus disease.
• Main Viral Hemorrhagic Fevers
  • Arenaviruses (Lassa), Ebola, Bunyaviruses (Congo-Crimean hemorrhagic fever virus and hantaviruses) and Flaviviruses (Yellow fever, Dengue, and Zika).

Chronic Latent Infections (Herpes Simplex Viruses - HSVs)

• These are transmitted in oral and genital secretions.
• HSV-1 typically presents with oral-labial herpes but can infrequently cause conjunctivitis, keratitis, encephalitis, herpetic whitlow, esophagitis, pneumonia or disseminated infection.
• HSV-2 commonly presents with genital herpes and can infrequently cause perinatal or disseminated infection. Histopathology in epithelial cells
• They form Cowdry type A intranuclear inclusions.
  • Large
  • Pink
  • Purple
• The viral infections contain both intact and disrupted virions.
• Exhibit cell fusion leading to multinucleated giant cells. A Tzanck smear: diagnostic test from blister fluid which may contain these giant cells.

Chronic Latent Infection: Varicella-Zoster Virus (VZV)

• First exposure causes chickenpox.
• Clinico pathologic features:
  • Identical characteristics across diseases
  • Vesicles fill with neutrophils and erode into shallow ulcers.
• Characteristic cytopathic effect on infected cells:
  • Nuclear homogenization
  • Intranuclear inclusions (Cowdry type A)
  • Inclusions are large and eosinophilic, separated from the nuclear membrane by a clear zone (halo).
  • Formation of multinucleated cells.
• Over time, vesicles become pustules, then rupture and heal. Clinical characteristics of chickenpox and Shingles
• Chickenpox:
  • Display characteristics such as fever, malaise, pruritic rash that starts on the head and spreads trunk and extremities
  • Skin lesions begin as maculopapular eruptions rapidly progressing to vesicles, then pustules that soon ulcerate.
  • Vesicles may also appear on mucous membranes, especially in the mouth.
• Shingles, unlike chickenpox, appears as unilateral.
  • Painful vesicular eruptions similar to the appearance of the aforementioned infection, though the unilateral pattern conforms to one dermatome
  • Pain may persist for months after the resolution of skin lesions.

Transforming Viral Infections: Oncogenic Viruses

• These are viruses with to transform infected cells.
  • They result to benign or malignant tumors.
• They promotes cell growth and survival.
• Viruses linked to human cancers include:
  • EBV (Epstein-Barr Virus)
  • HPV (Human Papillomavirus)
  • HBV (Hepatitis B Virus)
  • HTLV-1 (Human T-lymphotropic Virus 1) Common Human Oncoviruses, Cancer Types and occurrence.
  • Human papillomaviruses (HPV-16, HPV-18, and others): Cervical, vulvar, anal, vulva, vagina, penis, head and neck at 5.2%
  • Hepatitis B and hepatitis C viruses: Hepatocellular carcinoma around 4.9%
  • Human herpesvirus 8: Kaposi sarcoma and primary effusion lymphoma, about 0.9%
  • Epstein-Barr virus: Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal carcinoma, post-transplant, and lymphoproliferative disease (NA)
  • Human T-lymphotropic virus: Adult T-cell leukemia and lymphoma (NA)
  • Merkel cell cell polyoma virus: Merkel cell carcinoma (NA)
• High-risk HPVs (HPV-16 and HPV-18) implicated in squamous cell carcinomas that may arise on the: vagina, vulva, penis, anus, tonsillar, other oropharyngeal locations
• Low oncogenic risk HPVs are the cause of sexually transmitted vulvar, perineal, and perianal warts (condyloma acuminatum).
• HPV infection can be caused by vulnerable sites in the body:
  • The cervix, with its relatively large areas of immature squamous metaplastic epithelium.
  • Squamocolumnar junction of the anus.
  • Squamous cells of oropharyngeal tonsillar crypts.
• They cause changes through the viral E6 and E7 proteins:
  • Act a carcinogen depends on these viral components, which interfere with key tumor suppressor proteins like p53 and RB

Chronic Productive Infection

• Certain infections, the immune system cannot eliminate the virus.
  • Resulting in persistent viral replication and ongoing viremia.
• The high mutation rates in viruses like HIV and HBV contribute to their ability to evade the immune system control. Examples
  • HIV (Human Immunodeficiency Virus)
  • HBV (Hepatitis B Virus)

Learning Objectives: Bacteria

• Understand the bacterial mechanisms of cell and tissue damage.
  • Describe the ways bacteria induce cell and tissue damage.
  • Compare mechanisms across bacteria categories.
• Analyze the histologic patterns of tissue response in bacterial infections.
  • Identify histological reactions in response to bacterial infections.
    • Suppurative (Polymorphonuclear) Inflammation
    • Mononuclear and Granulomatous Inflammation
    • Cytopathic-Cytoproliferative Inflammation
    • Necrotizing Inflammation
    • Chronic Inflammation and Scarring

Bacterial mechanisms and Tissue Damage

• Streptococcus pyogenes damages via exotoxins (e.g., streptolysin and superantigens), causing tissue necrosis and immune system activation, and it is classified as Gram-positive (Cocci).
• Staphylococcus aureus generates tissue damage through exotoxins (e.g., toxic shock syndrome toxin) and enzyme production (e.g., hyaluronidase), resulting in tissue destruction, and this bacterium is Gram-positive (Cocci).
• Escherichia coli leads to epithelial cell damage and hemorrhagic colitis by releasing exotoxins (e.g. Shiga toxin) and it is a Gram-negative (Bacilli) bacterium.
• Pseudomonas aeruginosa causes tissue destruction and immune evasion producing proteases and exotoxins, and it is categorized as Gram-negative (Bacilli).
• Mycobacterium tuberculosis induces granulomatous inflammation and tissue fibrosis because of a chronic immune response, and it is an acid-fast bacilli.
• Clostridium tetani produces tetanospasmin toxin, which leads to muscle paralysis and tissue necrosis. Classifying this bacteria to be Gram-positive (Bacilli).
• Helicobacter pylori causes mucosal injury and ulcer formation from urease production, being Gram-negative (Spiral).
• Corynebacterium diphtheriae may display distinctive bull-neck appearance with upper respiratory involvement.